Hypoxia-Inducible Factor 2 Alpha (HIF2α) Inhibitors: Targeting Genetically Driven Tumor Hypoxia

Abstract

Tumors driven by deficiency of the VHL gene product, which is involved in degradation of the hypoxia-inducible factor subunit 2 alpha (HIF2α), are natural candidates for targeted inhibition of this pathway. Belzutifan, a highly specific and well-tolerated HIF2α inhibitor, recently received FDA approval for the treatment of nonmetastatic renal cell carcinomas, pancreatic neuroendocrine tumors, and central nervous system hemangioblastomas from patients with von Hippel-Lindau disease, who carry VHL germline mutations. Such approval is a milestone in oncology; however, the full potential, and limitations, of HIF2α inhibition in the clinic are just starting to be explored. Here we briefly recapitulate the molecular rationale for HIF2α blockade in tumors and review available preclinical and clinical data, elaborating on mutations that might be particularly sensitive to this approach. We also outline some emerging mechanisms of intrinsic and acquired resistance to HIF2α inhibitors, including acquired mutations of the gatekeeper pocket of HIF2α and its interacting partner ARNT. Lastly, we propose that the high efficacy of belzutifan observed in tumors with genetically driven hypoxia caused by VHL mutations suggests that a focus on other mutations that similarly lead to HIF2α stabilization, such as those occurring in neuroendocrine tumors with disruptions in the tricarboxylic acid cycle (SDHA/B/C/D, FH, MDH2, IDH2), HIF hydroxylases (EGLN/PHDs), and the HIF2α-encoding gene, EPAS1, are warranted.

Keywords: HIF2; VHL; belzutifan; cancer; hypoxia; hypoxia-inducible factor; inhibitor; mutation; neuroendocrine tumor; paraganglioma; pheochromocytoma; pseudohypoxia; resistance; sensitivity; targeted therapy.

Graphical abstract

Figure 1.

Mechanism of action of Belzutifan. Panel 1 depicts the HIF2α binding and dimerization with HIFβ (ARNT), the PAS (Per-ARNT-Sim) A domain and PAS (Per-ARNT-Sim) B domain. Also shown are key proline residues located at the ODD (oxygen-dependent degradation) domain. Panel 2 indicates where HIF2α acts by impeding the dimerization at the PAS domain. Panel 3 shows mutations in the PAS domains of HIF2α (G323E) and HIFβ (F446L) that restore dimerization rendering the tumor resistant to belzutifan.

Figure 2.

Diagram depicting HIF2α pathway, regulatory components and emerging indicators of sensitivity and resistance to HIF2α inhibitors. Abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; EPAS1, endothelial PAS domain-containing protein 1; FDA, United States Food and Drug Administration; FH, fumarate hydratase; HIF1β, hypoxia-inducible factor beta subunit; HIF2α, hypoxia-inducible factor 2 alpha subunit; HIF, hypoxia-inducible factor; HRE, hypoxia response element; IDH, isocitrate dehydrogenase; MDH2, malate dehydrogenase; mPPGL, metastatic pheochromocytoma and paraganglioma; pNET, pancreatic neuroendocrine tumor; PHD, prolyl hydroxylases; PPGL, pheochromocytoma and paraganglioma; SDH, succinate dehydrogenase; SDHAF2, succinate dehydrogenase assembly factor 2; TCA, tricarboxylic acid cycle; VHL, von Hippel–Lindau; αKG, α-ketoglutarate (Note: proteins and their domains not drawn to scale or location within sequence).